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The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment

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Abstract

Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment.

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Abbreviations

ADC:

Antibody-drug conjugates

Akt:

RAC-alpha serine/threonine-protein kinase

BiTE:

Bi-specific T cell engager

BRAF:

vRaf murine sarcoma viral oncogen

CaMKII :

Calmoduline kinase II

CAR-T:

Chimeric antigen receptor T cell

CCL:

Chemokine (C-C motif) ligand

CE:

Convergent extension

cGMP:

Cyclic guanosine monophosphate

CK2:

Casein kinase 2

CLL:

Chronic lymphocytic leukemia

CREB:

cAMP response element binding

CTL:

Cytotoxic T lymphocyte

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

CXCL:

Chemokine (C-X-C motif) ligand

DC:

Dendritic cells

Dkk:

Dickkopf

Dvl:

Dishevelled

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular regulated kinase

FOXC1:

Forkhead box C1

FOXM1:

Forkhead box transcription factor M1

IDO:

Indoleamine 2,3-dioxygenase-1

IKK:

IκB kinase

IL:

Interleukin

ICT:

Immune checkpoint therapy

IκB:

Inhibitor of NF-κB

JAK:

Janus kinase

JNK :

c-Jun N-terminal kinase

LPD:

Lipid-protamine-DNA

LPR:

Lipoprotein receptor–related protein

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

mAbs:

Monoclonal antibodies

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemoattractant protein 1

MMP:

Matrix metaloprotease

MSDC:

Myeloid-derived suppressor cells

MTOC:

Microtubule-organizing center

mTOR:

Mouse target of rapamycin

NETs:

Neutrophil extracellular traps

NF-κB:

Nuclear factor enhancer of immunoglobulin kappa light chain of activated B cells

NIK :

NF-κB inducing kinase

PCP:

Polar cell planarity

PD-1:

Programmed cell death receptor 1

PDE:

Phosphodiesterase

PI3K :

Phosphoinositide-3 kinase

PKA:

Protein kinase A

PKC:

Protein kinase C

PLC :

Phospholipase C

PORC:

Porcupine

RAC1:

Ras-related C3 botulinum toxin substrate 1

RANKL :

Receptor activator for NF-κB ligand

RAP1:

Ras-related protein 1

RHD:

Rel homology domain

Rho:

Ras homolog family member

RIP1:

Receptor interacting protein 1

ROR1/2:

RTK-like orphan receptor 1/2

ROS:

Reactive oxygen species

Ryk:

Receptor tyrosine kinase

shRNA :

Short hairpin RNA

Src:

Proto-oncogene tyrosine-protein kinase Src

STAT3:

Signal transducer and activator of transcription 3

TAK1 :

Transforming growth factor beta-activated kinase 1

TAMs:

Tumor-associated macrophages

TCF/LEF:

T cell factor/lymphoid enhancing factor

TGFβ:

Transforming growth factor beta

Th:

T helper cell

TLR :

Toll-like receptor

TME:

Tumor microenvironment

TNFα:

Tumor necrosis factor alpha

TRAF2:

TNF receptor associated factor 2

Treg:

Regulatory T cells

WIF1:

Wnt inhibitory factor 1

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Acknowledgments

We acknowledge the anonymous reviewer whose comments helped us to improve our manuscript. This research was supported by grants BID-PICT-2007-1010 and BID-PICT2011-1605 from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) and grants from Fundación Científica Felipe Fiorellino, Fundación Alberto Roemmers, and the Instituto Nacional de Cancer. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) provided fellowships to GB.

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  1. Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina

    Pablo Lopez-Bergami & Gastón Barbero

  2. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

    Pablo Lopez-Bergami & Gastón Barbero

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Lopez-Bergami, P., Barbero, G. The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment. Cancer Metastasis Rev 39, 933–952 (2020). https://doi.org/10.1007/s10555-020-09878-7

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